Cellular exposure to ionizing radiation (IR) activates a series of molecular signaling pathways, leading to cell cycle arrest, DMA repair, and/or apoptosis. Each signaling pathway has a characteristic molecular signature, defined by activated (phosphorylated) target proteins, and protein assembly in radiation-inducible nuclear foci. These convenient molecular signatures (biomarkers) can now be exploited in the development of diagnostic and therapeutic medical applications for human radiation exposure. In specific Aim 1, we will examine biomarkers in one radiation damage-response pathway (the Fanconi Anemia Pathway), to generate, test, and calibrate a biodosimeter in mouse and human models. We will obtain peripheral blood lymphocytes from human cancer patients undergoing Total Body Irradiation in order to test the sensitivity and specificity of the biodosimeter. In Specific Aim 2, we will conduct pathway-specific and general cell-based, small molecule drug screens, in order to identify novel radioprotective agents. Agents will be tested in murine and bone marrow progenitor assays for their cytoprotective effect. In specific aim 3, we will analyze a novel Reactive Oxygen Species (ROS) scavenger, WW-85, in murine and human radiation protection assays. We will test the ability of WW-85 to improve survival in the murine radiation LD50 model, lessen radiation-induced tissue damage, and improve the clonigenic survival of murine bone marrow stem cells. The work will be fortified by numerous interactions with the other projects (Livingston, Elledge, Sicinski) and with the Mouse Biology and Stem Cell Core (Core B), the Institute for Chemistry and Chemical Screening Core (Core C), and the Radiation Clinical Trial Core.